Stem Cells, Telomeres, and other Biological Fountains of Youth

If you believe certain musical groups, everybody wants to live forever (while ruling the world?). Our fascination with immortality is such that it’s a hallmark of mythology. In our daily lives, we obsess over staying young and healthy (or at least many advertisers and marketeers think we do, or at least that we obsess over how to appear young and healthy). And as a species we’ve funneled a lot of energy into searching for that one secret potion that will rejuvenate, that will indemnify us from aging and death. We might not be searching for a literal fountain of youth anymore, but there is plentiful, serious, high-quality biological research being done into how to slow or reverse the processes of aging. Not to mention all of the scams and hoaxes. Read on for five avenues of research that are or were tempting, and what they really say.

Antioxidants
I’m going to start with something you’ve probably heard of. Antioxidants. Antioxidants are things like vitamin C, vitamin E, and glutathione. They protect against scary “free radicals”, and have been hailed as something of a pop-culutral health panacea in recent years, whether or not they actually heal half the ills people claim they do.

So what are “free radicals” anyway, and why are they so scary? Well, it all comes down to viewing the aging of a human body as being equivalent to, say, the aging of an old iron tractor. The tractor breaks down due to wear and tear: in particular, it rusts. Maybe the human breaks down due to wear and tear, and rust, too.

Wait a minute, how would that even work? Well, just like oxygen (which is, in fact, the source of the ‘oxi’ part of ‘oxidants’ and the most common free radical) reacts with iron to cause it to rust, oxygen can react with your DNA and the proteins in your cells, too. And when it does, it can break them. Damaged DNA and proteins can’t function, which means that your body can’t function, and everything just sort of rusts and breaks over time.

The corollary here is if you could stop rusting, you could live forever.

Cutting the oxygen off at the source sounds tempting, but the reality is that these free radicals are natural byproducts of things that are kind of important for continued life. Like eating, and breathing.

Fortunately, your cells have mechanisms to get rid of free radicals before they do any damage. Vitamin C, vitamin E, and glutathione harmlessly react with, and disable, free radicals. And true to form, depleting cells of those antioxidants (and other ones) shortens lifespan. But creatures are very complicated. There are a lot of ways to break us and far fewer to fix us. Adding back more antioxidants (in the form of over-expressing proteins, since eating more vitamin C mostly just means you pee it out) doesn’t really increase the lifespan of flies. So whatever is causing your body to break down over time, it probably isn’t just not enough citrus.

Caloric restriction
So, if we can’t effectively increase lifespan by sopping up these free radicals, maybe we can at least limit our exposure. And that means exactly what I implied earlier: not eating.

Free radicals are the result of your metabolism: the faster your metabolism, the more free radicals you have. This correlates with lifespan: animals with slower metabolisms (relative to their size) also are generally very long-lived.

One great example of this is the naked mole rat, which lives in cold, oxygen-depleted subterranean tunnels, eats very little, and lives around 30 years (as opposed to about 3 for regular rats). Which brings up the question: if you could live 70 years out in the warm sunlight, eating a wide and varied diet, or 700 in a cold subterranean tunnel on a diet mostly consisting of root vegetables and your own feces, which would you choose? I think most of us would choose the 70 brightly-lit years.

Caloric restriction is something of a middle ground between Epicurus and the naked mole rat. It means providing a carefully designed diet that is rich in nutrients, so as to prevent malnutrition, but very low on calories. And while results are sometimes inconsistent, it seems like flies, and worms, and yeast, and rodents tend to live noticeably longer on low-calorie diets.

So what’s the catch? It probably doesn’t work in humans; there’s a host of conflicting data on whether caloric restriction helps with cardiovascular problems, with memory problems, and with anything else — no study on longevity has been done. It doesn’t work in primates: caloric restriction fails to raise the median lifespan of rhesus macaques. It appears to depend on the strain of mouse used — that’s what the image on the right shows. In fact, it doesn’t even work in flies, if you let them smell the food but not eat it. So if there is an effect for caloric restriction (and this one is actually a fairly well-documented and well-accepted hypothesis in the field) it certainly isn’t a simple “regular fasting for better living” kind of deal. Not for mammals, and especially not for humans.

Possibly even more damaging is that this entire hypothesis – that most aging is due to wear and tear via interaction with the world – is questionable. Researchers have found genes that, when disabled, increase the healthy lifespan of worms. This isn’t as crazy as it necessarily sounds — worms are one of the organisms where caloric restriction works best, so this oxidative stress hypothesis should definitely be in play. If even those little guys seem to have an inbred timer, what does that say about larger animals, like us, where caloric restriction itself doesn’t work so cleanly? In short, maybe aging isn’t always something that happens to us: it could be something we do to ourselves.

Telomeres
So let’s change gears. Let’s talk about what your body needs to do to just maintain it’s, say, 30-year-old self. Since you’re made of billions of cells, that means a lot of cell division.

Cells don’t just divide when you’re growing, cells have to divide to replenish tissues. A skin cell usually lasts about a month. A liver cell can last up to six if you’re lucky and careful. But both of them need to be replaced eventually, and that means some other cell somewhere has to divide.

Every time a cell divides, it has to replicate its DNA. But mammalian chromosomes are linear, and DNA polymerase (1) needs to start with something double-stranded and (2) can only go in one direction, so as it is chugging along the spiral of DNA it can’t make it all the way to both ends of both strands. Which means that if there weren’t some kind of cap on your chromosomes, you would lose genes every time your cells divided. Not good.

Eukaryotes generally get around this is by having ‘cap’ sequences called telomeres. Telomeres are strings of a short sequence repeated over and over again, and they loop in on themselves. This actually serves two functions: first, a telomere doesn’t have important gene or gene regulatory information, so if you lose a repeat or two it’s okay. And second, since the telomere loops in on itself, it doesn’t leave a naked end of double-stranded DNA anywhere. (Naked ends of double-stranded DNA tend to get stitched up with other pieces of DNA, and can result in mutations.) With long telomeres, replication can go on as normal. Without them, the cell will stop dividing rather than damage its DNA.

This image, via Wikimedia Commons and the National Cancer Institute, gives you some idea of the looping structure at the ends of a telomere, called a telosome.

So telomeres are great, and they let you go through a bunch of cell divisions without losing any of your important DNA. Woo! One hypothesis for why our body shuts down as we get older is that our cells just cannot keep dividing and replenishing themselves. Maybe that’s because they run out of telomere.

In fact, older people’s cells tend to have shorter telomeres. And artificially lengthening telomeres in mice and worms has yielded longer-lasting mice and worms. One way to do that is to add in an enzyme which can lengthen telomeres (it’s called telomerase and it’s common in stem cells and other cells that divide a lot). But there’s a bit of a problem here: adding in telomeres, and certainly adding back in telomerase, would remove one of the cues that cause cells to stop dividing. And we often want cells to stop dividing, especially in grownups; when they don’t, we end up with tumors. Lengthening your telomeres might make you live forever, or it might just give you cancer. Or maybe neither. (Probably not both, though.)

Stem Cells
Speaking of things that might just give you cancer, what if we used a cell rather than an enzyme to help boost your regenerative ability? Stem cells can divide like mad (they also have telomerase, and they also have, in theory, the means to shut it off in daughter cells). So can iPS cells – induced stem-like cells that we can make from, say, a skin sample or a blood sample. So you don’t have to add in an enzyme common in cancer cells in order to boost your body’s ability to replenish broken down cells. You could just add back some artificially rejuvenated cells.

In fact, stem cells have been suggested to treat a host of ills (many associated with aging, some not), as demonstrated by this image by Mikael Haggstrom (public domain) via Wikimedia Commons. Only bone marrow transplants have actually been tested, though.

There are a couple problems here. If we’re talking about using stem cell lines, which have been grown in culture and generally come from not-you people, then not only do we have to worry about all the weird things that happen in culture, we have to worry about the host rejecting the potentially therapeutic cells, or even possibly having a more serious immune response to them. So that’s no good. And if we’re using iPS cells, two of the factors that we have to add in to “reprogram” the cells are known to cause cells to turn into cancer. A lot of the mice that were born with even some of their cells deriving from these iPS cells got cancer. It turns out we can remove one of those cancer-y factors, and still get stemmy cells (although not as many and not as quickly). That seems to work better on the cancer front though: no cancer, at least in the natural lifespan of a mouse (around a year and a half). So, let’s chalk that one up as a ‘maybe’.

Transgenesis

I want to get back to genetics. (And not just because I’m a geneticist.) There are several reasons to think that there are genes that basically tell us when to die. Not least of these is the discovery I mentioned earlier: genes that, when removed or disabled, cause worms to live longer. The first genes identified that were acting as lifespan clock genes were chromatin modifiers: they are generally responsible for activating genes that should be active. And other people have looked in tissues of older organisms (worms, mice, humans) and found that there seems to be more transcriptional noise. Could it be that we lose control of our chromatin over time, and that causes us to age?

And what if a slightly-less-than-a-century lifespan is built in to humans? What could we do to change that?

There’s a certain amount of variation in lifespan, even among people. And it could well be genetic. For instance, living to 100 years old seems to run in families. Some researchers are looking at the genomes of people who reach 100 years old to see what makes them genomically special.

There’s a lot of variation in lifespan between species. And since we know some of the genes involved in predicting lifespan, maybe switching out a “short-lived” version for a “long-lived” version would increase lifespan. Surprisingly enough, this has been done, in worms. And even more surprisingly, it kind of worked.

Of course, adding in, say, a whale gene to a human in order to get us to live longer is (1) totally far out, technologically and (2) has a host of ethical ramifications that we would have to deal with. And so far, we’ve not been very good at actually dealing with the ethical ramifications of far-less problematic procedures, like prenatal genetic diagnosis. So it very well might be that a longer lasting human is possible, but isn’t really human. And where does that leave us, philosophically speaking?

Elizabeth Finn

Elizabeth is a geneticist working for a shady government agency and therefore obliged to inform you that all of the views presented in her posts are her own, and not official statements in any capacity. In her free time, she is an aerialist, a dancer, a clothing designer, and an author. You can find her on tumblr at madgeneticist.tumblr.com, on twitter at @lysine_rich, and also on facebook or google+.